This invention relates to the manufacture of a new cellulose excipient suitable for use as a filler, binder, and/or disintegrant in solid dosage forms and as a bodying agent or drug carrier in the development of topical formulations.
Solid compacts/tablets containing an active ingredient are prepared by either wet granulation or direct compression of a mixture of powders of various components. The number and types of components in a mixture depends on the desired properties of the drug, i.e., whether it is intended for immediate release or delayed and/or controlled release. Typically, the components include a drug, a filler (or diluent), a binder, a lubricant, and/or a glidant. A disintegrant is added if the tablet is intended for immediate release of the drug. The disintegrant promotes disintegration of the tablet into a fine powder by facilitation the penetration of water into the tablet mass. The filler is added to increase the bulk of the tablet to facilitate handling and manufacture. The use of a binder in the mixture increases the cohesiveness of powder and hence facilitates the formation of the tablet. Lubricants reduce the friction between the tablet and the die wall and therefore prevent sticking of the powder bed or tablets to the punches. Glidants, in contrast, are added to improve the flow characteristics of the materials. It is imperative that tabletting excipients be inexpensive, physiologically inert, physically and chemically stable, and compatible with the other tablet components.
The preparation of tablets by direct compression has steadily increased due to the ease of manufacture. Currently, in the United States, about 50% of tablets are made by the direct compression method. Of the various materials known, microcrystalline cellulose and powdered cellulose are perhaps the most commonly and widely used direct compression excipients. Microcrystalline celluloses are prepared by chemical disintegration of cellulose. Battista, O. A. (1950), Hydrolysis and Crystallization of Cellulose, Industrial and Engineering Chemistry 42:502-507; Battista U.S. Pat. No. 2,978,446.
In general, the process of preparing microcrystalline cellulose involves hydrolyzing the cellulose with an aqueous dilute solution of a strong mineral acid, with occasional or constant stirring, at an appropriate temperature for a period until the level off degree of polymerization (level-off DP) cellulose composed of crystalline aggregates is achieved. Powdered celluloses, in contrast, are produced by mechanical disintegration of cellulose, wherein the cellulose source is first compacted into a dense sheet, then either milled to produce fine particles or converted into granules and then fractionated by passage through one or more sieves to produce the desired cellulose granules (see e.g. Morse, U.S. Pat. No. 4,269,859) or alternatively, a finally divided form of cellulose is dispersed in water and then treated with an agglutinating agent. Filtration, followed by washing the agglutinated solid first with water and then with a water-miscible organic solvent, and subsequently, lyophilizing and freeze-drying yields the product (see e.g. Morse, U.S. Pat. No. 4,438,263 (1984)).
Currently, both microcrystalline cellulose and powdered cellulose are commercially available under various trade names in different grades and types. Of these, the most common and widely used microcrystalline and powdered cellulose products are sold under the tradenames Avicel(trademark) PH (FMC Corporation, Philadelphia, Pa.) and Solka Floc(trademark) (Penwest Company, Patterson N.Y.).
Recently, a new direct compression excipient called low crystallinity cellulose, having a degree of crystallinity value between 15 and 45% has been developed. See e.g. Banker and Wei, U.S. Pat. No. 5,417,984. It is produced by reacting cellulose with phosphoric acid first at room temperature for about an hour and then at 45-75xc2x0 C. for about 2-10.5 hours, followed by precipitation in water. Compared to microcrystalline cellulose (Avicel(copyright) PH-101), this material has been shown to possess superior properties as a binder.
The use of alkali metal hydroxides as swelling agents for cellulose has been extensively investigated. See e.g. Krassig, H. A. (1996), Cellulose Structure, Accessibility, and Reactivity, Gordon and Breach Science Publishers, Polymer Monographs, Volume 11. B. F. Wood, A. H. Conner, and C. G. Hill, Jr., A. Appl. Polym., 37:1371 (1989); C. Lin et al., ibid., 42, 417 (1991) and 45:1811 (1992). The emphasis of this research, however, has been (i) to convert cellulose into alkali cellulose for subsequent reactions to produce cellulose ethers, esters, xanthates, etc.; (ii) to improve the physical and chemical characteristics of cellulose, especially its reactivity with other agents; (iii) to study the hydrolysis kinetics of mercerized celluloses, (iv) for mercerizing treatments in textiles finishing to increase dye affinity, improve luster and smoothness, and achieve dimensional stability and raise tensile strength of fibers in the fabric, and (v) in the processing of cellulose hydrates fibers and films.
The present inventor has now discovered that soaking cellulose powder in an aqueous solution of alkali metal hydroxide and then precipitating it with ethanol and subsequently washing with water, or alternatively soaking cellulose pulp or sheet in an aqueous solution of alkali metal hydroxide, followed by washing with water and subsequently hydrolyzing with a dilute hydrochloric acid, produces a material that can be compressed into a tablet, with or without the aid of a binder, or used, optionally with other agents, in the development of a capsule dosage form. Further, the solid dosage form prepared in accordance with this invention rapidly disintegrates in water. The new cellulose excipient is also suitable as a drug carrier and/or bodying agent in the development of semisolid formulations with potential applications in pharmaceutical, food, cosmetic, and agricultural products.
Accordingly, it is a primary objective of the present invention to provide a cellulose excipient that can be used as a binder, a filler, and/or a disintegrant in the design of solid dosage forms.
It is a further objective of the present invention to provide a cellulose excipient that is directly compressible without the inclusion of a separate binder.
It is still a further objective of the present invention to provide a cellulose excipient that provides fast disintegrating properties.
Yet a further objective of the present invention is to provide a cellulose excipient that is economical to manufacture.
The method and means of accomplishing each of the above objectives as well as others will become apparent from the detailed description of the invention which follows hereafter.
The present invention describes a rapid and economical method of producing a cellulose excipient that can be compressed into a tablet without the aid of a binder. Compressed tablets made in accordance with this invention readily swell and disintegrate in water.
The cellulose excipient is prepared by (a) soaking a powdered source of cellulose in an alkali metal hydroxide, followed by precipitation with an alcohol, or (b) soaking a cellulose fiber or sheet source in an alkali metal hydroxide, then washing the swollen cellulose with water and subsequently reacting with a dilute mineral acid, first at room temperature and then at boiling temperature for a period of time sufficient to form a powder. The powdered product is then filtered and washed. The wet cake of the new excipient can be resuspended in water, or hydroalcoholic solutions, and mixed with adequate amounts of a suspending agent to produce a variety of stable dispersions. Such dispersions of the cellulose excipient can also be readily converted to cellulose beads or formulated into topical pharmaceutical and/or cosmetic compositions to treat a variety of skin disorders.